Diarylethene‐Based Photoswitchable Inhibitors of Serine Proteases

Abstract

A bicyclic peptide scaffold was chemically adapted to generate diarylethene‐based photoswitchable inhibitors of serine protease Bos taurus trypsin 1 (T1). Starting from a prototype molecule—sunflower trypsin inhibitor‐1 (SFTI‐1)—we obtained light‐controllable inhibitors of T1 with Ki in the low nanomolar range, whose activity could be modulated over 20‐fold by irradiation. The inhibitory potency as well as resistance to proteolytic degradation were systematically studied on a series of 17 SFTI‐1 analogues. The hydrogen bond network that stabilizes the structure of inhibitors and possibly the enzyme–inhibitor binding dynamics were affected by isomerization of the photoswitch. The feasibility of manipulating enzyme activity in time and space was demonstrated by controlled digestion of gelatin‐based hydrogel and an antimicrobial peptide BP100‐RW. Finally, our design principles of diarylethene photoswitches are shown to apply also for the development of other serine protease inhibitors.

Photoresponsive Small Molecule Inhibitors for the Remote Control of Enzyme Activity

“…The photochromic DTE moiety has also been utilised as a means to achieve photoswitchable inhibition of serine proteases (Figure 9). [50] Known bicyclic peptidic inhibitor, SFTI‐1, of the serine protease Bos taurus typsin 1 (T1) consists of two loops stabilised by a disulfide bridge, whereby the reactive loop binds the serine protease. The DTE‐derived peptidic inhibitor 46 was realised by merging the photoswitching unit into the structural loop of SFTI‐1, which does not interact with the active site of the enzyme.…”

Near‐Infrared Phosphorescent Switch of Diarylethene Phenylpyridinium Derivative and Cucurbit[8]uril for Cell Imaging

“…[17][18][19][20] For example, it has been reported that diarylethene and its derivates can undergo efficient and reversible photochromism when irradiated with UV and visible light, ultimately allowing control of the luminescence of such compounds. [21][22][23][24][25] The combination of NIR phosphorescence and photochromism in a single diarylethene molecule could therefore render such a system widely applicable in various fields. However, to the best of our knowledge, photo-controlled pure organic NIR phosphorescence has yet to be reported in solution.…”

Cystine Knot Peptides with Tuneable Activity and Mechanism

“…[13][14][15] These strategies have been successfully applied to diverse targets, including enzymes [1,3,7] and transmembrane proteins, [6,12] as well as peptides or proteins that modulate the activity of these targets, such as enzyme inhibitors. [16][17][18] For the latter, tuneable activity is particularly useful as it can shift the inhibitor's influence on its intended target or pathway. [16][17][18] However, efforts to engineer peptide-based inhibitors with switchable activity have been largely confined to relatively short peptides with non-complex topologies.…”

“…[16][17][18] For the latter, tuneable activity is particularly useful as it can shift the inhibitor's influence on its intended target or pathway. [16][17][18] However, efforts to engineer peptide-based inhibitors with switchable activity have been largely confined to relatively short peptides with non-complex topologies.…”

“…The new possibilities that can be realised with tuneable peptides and proteins have inspired several approaches for modulating their activity using light via photocaging [1–5] or photoswitching, [6–10] changes in pH, [11, 12] or competing binding interactions [13–15] . These strategies have been successfully applied to diverse targets, including enzymes [1, 3, 7] and transmembrane proteins, [6, 12] as well as peptides or proteins that modulate the activity of these targets, such as enzyme inhibitors [16–18] . For the latter, tuneable activity is particularly useful as it can shift the inhibitor's influence on its intended target or pathway [16–18] .…”